Christine Brostjan

Publications (44) View all

• Article: Neoadjuvant bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation.

  P Starlinger, L Alidzanovic, D Schauer, T Maier, C Nemeth, B Perisanidis, D Tamandl, B Gruenberger, T Gruenberger, C Brostjan
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  ABSTRACT: Background:When anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is applied in neoadjuvant treatment of colorectal cancer patients with liver metastasis, 5-6 weeks between last bevacizumab dose and liver resection are currently recommended to avoid complications in wound and liver regeneration. In this context, we aimed to determine whether VEGF is inactivated by bevacizumab at the time of surgery.Methods:Fifty colorectal cancer patients with liver metastases received neoadjuvant chemotherapy±bevacizumab supplementation. The last dose of bevacizumab was administered 6 weeks before surgery. Plasma, subcutaneous and intraabdominal wound fluid were analysed for VEGF content before and after liver resection (day 1-3). Immunoprecipitation was applied to determine the amount of bevacizumab-bound VEGF.Results:Bevacizumab-treated individuals showed no increase in perioperative complications. During the entire monitoring period, plasma VEGF was inactivated by bevacizumab. In wound fluid, VEGF was also completely bound by bevacizumab and was remarkably low compared with the control chemotherapy group.Conclusion:These data document that following a cessation time of 6 weeks, bevacizumab is fully active and blocks circulating and local VEGF at the time of liver resection. However, despite effective VEGF inactivation no increase in perioperative morbidity is recorded suggesting that VEGF activity is not essential in the immediate postoperative recovery period.
  British Journal of Cancer 07/2012; 107(6):961-6. · 5.04 Impact Factor
• Article: Systemic effects of anti-VEGF therapy – Mini-review

  P. Starlinger, K. Gebhardt, T. Grünberger, C. Brostjan
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  ABSTRACT: BACKGROUND: Systemic therapies targeting the pro-angiogenic mediator vascular endothelial growth factor A (VEGF) have successfully been applied in the treatment of various cancers, but response to therapy seems to be short-lived. METHODS: Current concepts of resistance mechanisms to anti-VEGF therapy are being reviewed. RESULTS: Initial responders to VEGF-targeted therapy seem to relapse after a few months and numerous patients do not respond to therapy at all. Several potential resistance mechanisms have been identified such as the induction of fibroblast growth factor or the regulation of the angiogenesis inhibitor thrombospondin-1. CONCLUSIONS: Escape mechanisms to anti-VEGF therapy seem to limit the therapeutic efficacy. Furthermore, these compensatory mechanisms may also explain why patients receiving neoadjuvant anti-VEGF treatment do not suffer from wound healing complications following surgery. GRUNDLAGEN: Patienten mit fortgeschrittenen Krebserkrankungen profitieren von anti-angiogenetischer Therapie, die die Gefäßbildung im Tumor über die Blockade von Vascular Endothelial Growth Factor A (VEGF) unterbindet. Jedoch scheint der therapeutische Nutzen limitiert in seiner Wirkungsdauer. METHODIK: Aktuelle Konzepte der Resistenzmechanismen betreffend anti-VEGF Therapie werden vorgestellt und diskutiert. ERGEBNISSE: Initiales Ansprechen auf VEGF-Blockade ist in einem Großteil der Patienten begrenzt auf einige Monate. Weiters spricht eine erhebliche Anzahl von Patienten von Beginn an nicht auf die Therapie an. Es konnten bereits einige potentielle Resistenzmechanismen identifiziert werden. In diesem Zusammenhang wurde beispielsweise die Induktion von Fibroblasten Wachstumsfaktor oder die Regulation des Angiogenesehemmers Thrombospondin-1 charakterisiert. SCHLUSSFOLGERUNGEN: Kompensationsmechanismen diverser Angiogenesefaktoren scheinen zur Resistenz gegenüber VEGF-Blockade zu führen und damit den therapeutischen Langzeiterfolg bei Krebspatienten zu verhindern. Weiters könnten diese Resistenzmechanismen die Beobachtung erklären, dass bei neoadjuvantem Einsatz von VEGF-Hemmern keine Wundheilungsstörungen nach chirurgischem Eingriff auftreten. KeywordsAnti-angiogenic therapy-Bevacizumab-Therapy resistance-Wound healing SchlüsselwörterAnti-angiogenetische Therapie-Bevacizumab-Therapieresistenz-Wundheilung
  European Surgery 04/2012; 42(1):12-16. · 0.28 Impact Factor
• Article: Thrombospondin-1: a unique marker to identify in vitro platelet activation when monitoring in vivo processes.

  P Starlinger, H P Moll, A Assinger, C Nemeth, K Hoetzenecker, B Gruenberger, T Gruenberger, I Kuehrer, S F Schoppmann, M Gnant, C Brostjan
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  ABSTRACT: Measuring platelet activation in patients has become a potent method to investigate pathophysiological processes. However, the commonly applied markers are sensitive to detrimental influences by in vitro platelet activation during blood analysis. Protein isoforms of platelet-derived thrombospondin-1 (TSP-1) were investigated for their potential to identify in vitro platelet activation when monitoring in vivo processes. TSP-1 was determined in plasma, serum or supernatant of purified platelets by ELISA and immunoblotting and was compared with standard markers of platelet activation. A collective of 20 healthy individuals and 30 cancer patients was analyzed.  While in vitro platelet degranulation led to a selective increase in the 200-kDa full-length molecule, an in vivo process involving platelet activation such as wound healing resulted in the predominant rise of the 140-kDa TSP-1 protein. The physiological ratio of circulating TSP-1 variants was determined and a cut-off level at 1.0 was defined to identify plasma samples with artificial in vitro platelet activation exceeding the cut-off level. In contrast, cancer patients known to frequently exhibit increased in vivo activation of platelets presented with a significantly decreased ratio of TSP-1 variants as compared with healthy volunteers. In comparison to standard platelet markers, TSP-1 constitutes a sensitive and stable parameter suited to monitor in vitro platelet activation. The analysis of TSP-1 protein isoforms further offers a valuable tool to reliably discriminate between in vitro and in vivo effects, to exclude variability introduced during blood processing and improve clinical monitoring.
  Journal of Thrombosis and Haemostasis 08/2010; 8(8):1809-19. · 5.73 Impact Factor
• Article: Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma.

  Thomas Bachleitner-Hofmann, Josef Friedl, Michaela Hassler, Hubert Hayden, Peter Dubsky, Monika Sachet, Erwin Rieder, Roswitha Pfragner, Christine Brostjan, Stefan Riss, Bruno Niederle, Michael Gnant, Anton Stift
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  ABSTRACT: Immunotherapy with autologous dendritic cells (DCs) loaded with tumor lysate(s) from allogeneic tumor cell lines is a novel strategy to induce immune responses in cancer patients. We report on a pilot trial of autologous DCs pulsed with tumor cell lysate derived from allogeneic medullary thyroid carcinoma (MTC) cell lines in patients with metastatic MTC. The purpose of this study was to assess the safety, resulting immune responses and clinical activity of the DCs. DCs were injected into a groin lymph node at 3-week intervals. Monitoring included serial calcitonin tumor marker measurements, radiological imaging and immunological in vitro tests (T-cell interferon-gamma detection assay, T-cell cytotoxicity assay). Ten patients (median age 47 years, range 29-77) were enrolled. DC vaccinations were well-tolerated and safe. After a median follow-up of 11 months, (range 7-26), 3 (30%) of 10 patients had stable disease, while 7 (70%) of the patients progressed during treatment. In 2 patients with stable disease, calcitonin decreased below treatment levels, paralleled by a T-cell-mediated immune response. Notably, treatment with DCs pulsed with a combination of different tumor cell lysates was followed by a calcitonin decrease in 4 patients who had previously experienced a calcitonin increase during monotherapy with DCs pulsed with a single lysate. Allogeneic tumor cell lysate-based DC immunotherapy is well-tolerated and safe. Combined treatment with different tumor cell lysate-pulsed DCs increases the likelihood of a calcitonin tumor marker response and should therefore be preferred over monotherapy with DCs pulsed with a single lysate.
  Oncology Reports 07/2009; 21(6):1585-92. · 1.84 Impact Factor
• Article: Elevated levels of circulating endothelial progenitor cells in head and neck cancer patients.

  Markus Brunner, Dietmar Thurnher, Gregor Heiduschka, Matthaeus Ch Grasl, Christine Brostjan, Boban M Erovic
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  ABSTRACT: Measurement of circulating endothelial cells (CECs) and progenitor cells (EPCs) has potential as a surrogate marker for monitoring anticancer treatment. This study evaluated the significance of CECs and EPCs in the blood of patients with head and neck squamous cell carcinoma. In a prospective trial fresh blood samples from 22 tumor patients and 18 controls were tested using multiparametric flow-cytometry. CECs were defined as CD31(+)/CD146(+) and CD45(-)/7AAD(-). EPCs were defined as CD133(+)/KDR(+) and CD3(-)/CD19(-)/CD33(-)/7AAD(-). Median levels (min/max) of CECs in the tumor group were 2 (0/5) at the time of diagnosis, 1 (0/5) 1 year after therapy and 2 (0/6) in the control cohort. Median levels of EPCs were 5 (1/41) before and 10 (0/21) after treatment in the tumor group compared to 2 (0/7) in the control cohort (P < 0.001 and P = 0.03). CEC and EPC levels showed no apparent correlation with tumor size and response to radiotherapy after 18 months of observation. In this pilot study CD133(+)/KDR(+) EPCs were significantly elevated in head and neck tumor patients before and after therapy. Our results warrant further studies on the use of EPCs as a surrogate marker for anticancer therapies in these patients.
  Journal of Surgical Oncology 10/2008; 98(7):545-50. · 2.10 Impact Factor